Preparation and analytical characterization of 1‐(1‐phenylcyclohexyl)piperidine (PCP) and 1‐(1‐phenylcyclohexyl)pyrrolidine (PCPy) analogues

Abstract

Classic examples of psychoactive arylcycloalkylamines include ketamine and 1-(1-phenylcyclohexyl)piperidine (PCP) and many others serve as important structural templates for neuropharmacological research. The recent emergence of PCP analogues that can be obtained from internet retailers requires the implementation of appropriate monitoring strategies for harm reduction purposes. Access to analytical data plays a key part when encountering these substances, especially if reference material is not available. The present study describes the synthesis of three substituted 1-(1-phenylcyclohexyl)piperidines, (3-MeO-, 4-MeO- and 3-Me-PCP) and three substituted 1-(1-phenylcyclohexyl)pyrrolidine analogues (3-MeO-, 4-MeO- and 3-Me-PCPy). Analytical characterizations of all six arylcyclohexylamines and their primary 1-phenylcyclohexanamine intermediates included gas chromatography ion trap electron- and chemical ionization and high resolution mass spectrometry, liquid chromatography electrospray hybrid triple-quadrupole linear ion trap tandem mass spectrometry, infrared, diode array detection and (1) H and (13) C nuclear magnetic resonance (NMR) spectroscopy. Solvent (CDCl3 vs. d6 -DMSO) and protonation effects (free bases vs hydrochloride salts) were studied in order to investigate the impact on shifts and splitting patterns, for example, when attempting to assign separate axial and equatorial proton chemical shifts of NMR spectra. Differentiation between the isomeric 3-MeO-/4-MeO-PCP and PCPy analogues was feasible under mass spectral conditions. Gas chromatography analysis appeared to induce notable degradation of the 4-MeO-substituted analytes, especially when dealing with the HCl salts which led to the detection of the substituted 1-phenylcyclohex-1-ene nucleus. This phenomenon was observed to be less pronounced with the 3-MeO isomers, possibly due to the resonance properties of the para-methoxy group followed by more facile elimination of the amine.

Preparation and characterization of the ‘research chemical’ diphenidine, its pyrrolidine analogue, and their 2,2‐diphenylethyl isomers

“…This was consistent with previous CI-IT-MS studies of a range of PCP and PCPy analogues where the piperidine and pyrrolidine fragments have also been detected. [19] A mass spectral comparison between the 1-(1,2-diphenylethyl) and 1-(2,2-diphenylethyl) compounds (1)/(3) and (2)/(4) highlighted that differentiation between isomers was possible under EI-and CI conditions. For example, the diphenidine isomer (2) gave an iminium base peak at m/z 98 instead of m/z 174 observed for diphenidine ( Figures 3E and 4).…”

“…This procedure was also employed by Berger et al for the preparation of diphenidine and its single enantiomers [14] and it previously provided convenient access to the preparation of PCP and PCPy analogues. [19] The synthesis of diphenidine was reported first in 1924 and was based on a modified Bruylanys reaction between benzylmagnesium bromide and the corresponding α-arylamino nitrile. [21] A number of additional synthetic routes to diphenidine have been described and include modified Mannich-type reactions employing benzyl bromide, piperidine and benzaldehyde [30] and gold-catalyzed hydroamination of diphenylacetylene with piperidine.…”

“…Although these analogues have been introduced to the market, the availability of analytical data has been less abundant. [7,19] For this reason, it was decided to prepare the two corresponding pyrrolidine derivatives of these diphenylethylamines, i.e. 1-(1,2-diphenylethyl)pyrrolidine (1,2-DEPy) (3) and 1- (2,2-21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 F o r P e e r R e v i e w 4 diphenylethyl)pyrrolidine (2,2-DEPy) (4), respectively.…”

From PCP to MXE: a comprehensive review of the non‐medical use of dissociative drugs

“…These materials originally researched by hugo24 and fastandbulbous were absent from the scientific literature at the time. [186] 3-MeO-PCP continues to be available from a number of non-UK-based RC vendors as of March 2014. Both compounds are active, inducing characteristic dissociative intoxication at 5-10 mgs via oral ingestion and insulfation.…”

Syntheses, analytical and pharmacological characterizations of the ‘legal high’ 4‐[1‐(3‐methoxyphenyl)cyclohexyl]morpholine (3‐MeO‐PCMo) and analogues

“…The syntheses of the primary amine intermediates were performed using a modified Geneste route (Figure ) as described previously . Reactions starting from the primary amine intermediate to yield the morpholine ring products were carried out in a CEM Discover SP microwave synthesizer.…”